Synthesis of (2R)-2-bromodehydroquinic acid and(2R)-2-fluorodehydroquinicacidhairsp;

摘要

J. Chem. Soc. Perkin Trans. 1 1997 625 Synthesis of (2R)-2-bromodehydroquinic acid and (2R)-2-fluorodehydroquinic acid † Michael K. Manthey,‡ Concepción González-Bello § and Chris Abell * Cambridge Centre for Molecular Recognition University Chemical Laboratory Lensfield Road Cambridge CB2 1EW UK (2R)-2-Bromodehydroquinic acid and (2R)-2-fluorodehydroquinic acid † have each been synthesised in six steps from quinic acid via the common intermediate 6. The syntheses exploit the selective protection of the 4-hydroxy group of the quinic acid lactone 3 with tert-butyldimethylsilyl chloride. The shikimate pathway to the aromatic amino acids 1 is a target for herbicides and antimicrobial agents. The broad spectrum post-emergence herbicide glyphosate acts by inhibiting 5- enolpyruvyl shikimate 3-phosphate (EPSP) synthase,2 and recently the antimicrobial action has been demonstrated for (6S)-6-fluoroshikimic acid.3 Interest in this pathway has resulted in the synthesis of many analogues of pathway intermediates especially derivatives of shikimic acid.We are interested in dehydroquinic acid analogues substituted at C-2 as potential inhibitors of 3-dehydroquinate dehydratase. Here we describe the synthesis of (2R)-2-bromodehydroquinic acid 8 and (2R)-2-fluorodehydroquinic acid 10.† These are the first syntheses of 2-substituted dehydroquinic acid derivatives. Bartlett and co-workers have recently reported the synthesis of the corresponding 2-bromoshikimic acid 4 and 2-fluoroshikimic acid.5 (2R)- and (2S)-2-Hydroxyquinic acids and (2R)-2-bromoquinic acid have also been synthesised.6 Quinic acid was used as an inexpensive chiral advanced intermediate.The required transformations are selective oxidation at C-3 and introduction of the halogenic substituent at C-2. However to achieve this it is necessary to protect the other functionality present in quinic acid (Scheme 1). The first step involves the quadruple protection of quinic acid 1 in the toluene-p-sulfonic acid catalysed reaction with benzaldehyde.7 Azeotropic removal of the water gave the benzylidene acetal 2 as a 2.2 1 mixture of diastereoisomers in 79% yield. The major isomer was isolated after recrystallisation from diethyl ether. The benzylidene centre was shown to have the Rconfiguration by observation of NOEs from H-4 and H-5 to the benzylidene hydrogen in the 1H NMR spectrum. The benzylidene protecting group was removed by catalytic hydrogenation over 10% palladium on charcoal to give quinic acid lactone 3 in 93% yield.It is possible to convert 1 directly into 3 8 but the two step procedure used has been found to be experimentally preferable. The selective protection of the C-4 hydroxy group of 3 was achieved using tert-butyldimethylsilyl (TBDMS) chloride. Reaction of 3 with TBDMS chloride in N,N-dimethylformamide (DMF) at 0 8C for 6 h gave a mixture of the monoprotected compounds 4 and 5 in a ratio of 97 3 (combined yield 82%). However if the reaction was carried out at 90 8C the selectivity was reversed and the product ratio was then 1 2 † IUPAC names (1S,2R,4S,5R)-2-bromo-1,4,5-trihydroxy-3-oxocyclohexanecarboxylic acid and (1S,2R,4S,5R)-2-fluoro-1,4,5-trihydroxy-3- oxocyclohexanecarboxylic acid respectively.‡ Present address Department of Biochemistry The University of Sydney Sydney NSW 2006 Australia. § Present address Departamento de Química Orgánica Facultad de Ciencias Augas Férreas Polígono Fingoi 27002 Lugo Spain. in favour of the required C-4 silyl ether (combined yield 84%). Submission of the kinetic product 4 to the higher temperature conditions resulted in it being converted to a mixture of 4 and 5. The structure of 5 was assigned after careful NMR spectroscopic studies. The 1H NMR spectrum recorded under rigorously dry conditions showed an 11.3 Hz coupling between 5-H and a hydroxy proton. Furthermore NOE difference spectroscopy indicated significant enhancements of 3-H and 5-H and in the TBDMS protons upon irradiation of 4-H.Conversely irradiation of 5-H resulted in enhancement of 4-H 6eq-H and the C-5 hydroxy proton. Irradiation of 3-H resulted in enhancement of 4-H 2eq-H 2ax-H and the TBDMS protons. These observations and subsequent chemical transformations con- Scheme 1 Reagents conditions and yields (i) PhCHO 4-TsOH toluene reflux (74%); (ii) H2 [10%]Pd/C AcOH room temp. (94%); (iii) TBDMSCl DMAP Et3N Bu4NI 0 8C (79%); (iv) TBDMSCl DMAP Et3N Bu4NI 90 8C (54%); (v) PDC 4 Å molecular sieves CH2Cl2 room temp. (87%) 626 J. Chem. Soc. Perkin Trans. 1 1997 firmed the location of the silyl group in 5 and hence the corresponding location in 4. The secondary hydroxy group in 5 was readily oxidised using either pyridinium chlorochromate (PCC) tetrapropylammonium perruthenate–N-methylmorpholine N-oxide (TPAP– MNO) or pyridinium dichromate (PDC) in the presence of 4 Å activated molecular sieves.The latter reaction proceeded in the highest yield (87%) to give the ketone 6. This compound is acidsensitive and so was purified by recrystallisation from hexane. Ketone 6 is the key intermediate in the synthesis of both (2R)-2-bromodehydroquinic acid 8 and (2R)-2-fluorodehydroquinic acid 10 (Scheme 2). For the synthesis of (2R)-2- bromodehydroquinic acid the bromine is introduced stereoselectively using dioxane dibromide10 to afford the axiallybrominated derivative 7 (89%). In the NMR spectrum of 7 the axial bromine causes a downfield shift in the signal for the hydrogen 1,3-diaxial to it (2ax-H) from d 2.86 in 6 to d 3.33. The isolation of a single diastereoisomer of 7 is presumed to be due to preferential bromination on the side of the ketone 6 opposite to the bridging lactone group.The TBDMS protecting group of 7 was removed and the lactone opened by mild acid hydrolysis (HOAc–H2O–THF) at 40 8C to give the required (2R)-2-bromodehydroquinic acid 8 in 95% yield. The equatorial position of the bromine was confirmed by NMR spectroscopy. Irradiation of 2-H led to enhancement of the signals for 4-H (6%) and 6ax-H (4%). Correspondingly irradiation of 4-H enhanced the signals for 2-H (6%) and 6ax-H (3%). The configuration at C-2 (C-6 in compound 7) is unchanged in going from 7 to 8 it is simply the cleaving of the lactone which allows the ring to flip to the other chair conformation. (2R)-2-Fluorodehydroquinic acid 10 was synthesised from the protected ketone 6 in two steps.The silyl enol ether was made using trimethylsilyl trifluoromethanesulfonate and reacted directly with Selectfluor‚ 9 in DMF to give the protected fluoro ketone 9 in 89% yield. This was deprotected in aqueous Scheme 2 Reagents conditions and yields (i) Br2?dioxane Et2O room temp. (89%); (ii) AcOH THF H2O 40 8C (95%); (iii) (a) TMSOTf Et3N toluene reflux (b) Selectfluor‚ DMF room temp. (89%); (iv) AcOH H2O 50 8C (90%) acetic acid to give 10 (90%). The equatorial position of the fluorine was confirmed by NMR spectroscopy. The fluorine has a geminal coupling to 2-H of 47 Hz and a W-coupling to 6eq-H of 8 Hz. Irradiation of 2-H led to enhancement of the signals for 4-H (6%) and 6ax-H (4%). Correspondingly irradiation of 4-H enhanced the signals for 2-H (6%) and 6ax-H (3%). (2R)-2-Bromodehydroquinic acid and (2R)-2-fluorodehydroquinic acid are stable in either water or acetone at 4 8C.However upon heating to over 80 8C quantitative dehydrohalogenation and aromatisation yield 3,4,5-trihydroxybenzoic acid. The syntheses of (2R)-2-bromodehydroquinic acid 8 and (2R)-2-fluorodehydroquinic acid 10 are both short and highyielding especially in light of the problems encountered in the synthesis of the related 2-bromoshikimic acid 4 and 2-fluoroshikimic acid.5 Preliminary studies show that both 8 and 10 are inhibitors for dehydroquinate dehydratase the third enzyme on the shikimate pathway. Full details of these biological studies will be published elsewhere. Experimental General NMR Spectra were recorded on either a Bruker WM-250 WM-400 DPX-250 or DPX-500 NMR spectrometer in deuteriated solvents with tetramethylsilane as an internal standard.J Values are given in Hz. Melting points were determined on a Buchi 510 or Reichert melting points apparatus and are uncorrected. IR Spectra were recorded on a Perkin-Elmer 1310 infrared spectrometer or a 1710 Fourier Transform spectrometer as Nujol mulls unless otherwise indicated. Mass spectra were recorded on a Kratos MS890 double-focussing magnetic sector apparatus (for EI CI and FAB). Optical rotations were measured on an AA-10 automatic polarimeter (Optical Activity Ltd.); [a]D values are given in 1021 deg cm2 g21. All organic solvents were freshly distilled prior to use. Dichloromethane triethylamine toluene and hexane were dried over calcium hydride. Methanol was dried over potassium carbonate.Diethyl ether was dried over lithium aluminium hydride. Analytical thin layer chromatography was carried out on commercial Kieselgel 60 0.25 mm silica plates. Spots were visualised by UV absorbance at 254 nm iodine potasium permanganate(VII) or cerium molybdate solution. Flash chromatography was carried out using 230–400 mesh Kieselgel 60 silica. The carboxylic acids were purified by HPLC on a preparative (300 mm × 16 mm) Bio-Rad Aminex Ion Exclusion HPX-87H Organic Acids column eluting with aqueous formic acid (50 mM) at a flow rate of 1.2 cm3 min21 with the UV detector set at 277 nm. (1S,3R,4R,5R)-4,5-Benzylidenedioxy-1-hydroxycyclohexane- 1,3-carbolactone 2 A mixture of (2)-quinic acid 1 (4.94 g 25.7 mmol) distilled benzaldehyde (3.9 cm3 38.6 mmol) and toluene-p-sulfonic acid (253 mg 1.3 mmol) was heated at reflux in toluene (50 cm3) in an apparatus fitted with a Dean–Stark trap for 22 h.The solution was allowed to cool and the toluene evaporated at reduced pressure. The oily residue was taken up in diethyl ether and decanted from the solid. The crude mixture was purified by column chromatography on silica gel eluting with ethyl acetate– light petroleum (bp 40–60 8C) (1 1) to give the benzylidene carbolactones 2 (5.31 g 79%) as a mixture of diastereoisomers at the benzylic carbon in a ratio of 2.2 1. On cooling the viscous oil crystallised. Recrystallisation from diethyl ether gave the major diastereoisomer (with the R configuration at the benzylic centre) of carbolactone 2 as white needles mp 100–101 8C (lit.,7 95 8C); RF 0.46 [ethyl acetate–light petroleum (bp 40–60 8C) 1 1] (Found C 63.9; H 5.4.C14H14O5 requires C 64.1; H 5.4%); nmax(CH2Cl2)/cm21 3540 (free OH) 3420 (H-bonded OH) 1800 (C]] O) and 1470 (Ar C–C); dH(250 MHz; CDCl3) 7.51–7.36 (5 H m Ph) 5.75 (1 H s PhCHO2) 4.81 (1 H dd J J. Chem. Soc. Perkin Trans. 1 1997 627 6.1 and 2.1 3-H) 4.52 (1 H td J 7.0 and 2.7 5-H) 4.37 (1 H dt J 7.0 and 2.1 4-H) 2.91 (1 H br s OH) 2.78 (1 H d J 11.9 2ax-H) 2.46 (1 H ddd J 15.1 7.0 and 2.1 6eq-H) 2.36 (1 H dd J 15.1 and 2.7 6ax-H) and 2.34 (1 H ddt J 11.9 6.1 and 2.1 2eq-H); dC(62 MHz; CDCl3) 178.9 135.4 129.9 128.6 126.6 103.7 75.5 72.9 72.7 71.4 37.7 and 34.4; m/z (EI+) 262 (M+) 261 [(M 2 H)+] and 105 [(PhCO)+] (Found M+ 262.0820. C14H14O5 requires M 262.0841). (1S,3R,4R,5R)-1,4,5-Trihydroxycyclohexane-1,3-carbolactone 3 To 500 mg of palladium on charcoal (10%) under a hydrogen atmosphere was added glacial acetic acid (10 cm3).After 10 min a solution of the acetal 2 (5 g 19.0 mol) in glacial acetic acid (40 cm3) was added. The system was evacuated and kept under a hydrogen atmosphere until reduction was complete as judged by TLC (48 h). The hydrogen was evacuated the suspension filtered over Celite and washed with acetic acid (50 cm3) and methanol (50 cm3). The solvent was removed under reduced pressure and the product was recrystallised from acetic acid to afford 3.09 g (94%) of the hydroxylactone 3 as white prisms mp 184–185 8C (lit.,8 185–189 8C); nmax/cm21 3000–3560 (OH) and 1780 (C]] O); dH(250 MHz; CD3OD) 4.91 (3 H br s OH) 4.75 (1 H dd J 4.9 and 6.0 3-H) 4.02 (1 H dd J 4.5 and 4.9 4-H) 3.74 (1 H ddd J 4.5 6.6 and 11.3 5-H) 2.51 (1 H d J 11.5 2ax-H) 2.26 (1 H ddd J 2.9 6.0 and 11.5 2eq-H) 2.07 (1 H ddd J 6.6 2.9 and 11.6 6eq-H) and 1.91 (1 H dd J 11.3 and 11.6 6ax-H); dC(62 MHz; CD3OD) 179.5 77.6 73.1 67.3 66.8 40.0 and 37.8.Selective monosilylation of the trihydroxylactone 3 Method A. To a stirred solution of the hydroxylactone 3 (1.83 g 10.52 mmol) 4-dimethylaminopyridine (DMAP) (180 mg 1.47 mmol) and butylammonium iodide (194 mg 0.53 mmol) in dry DMF (17 cm3) and dry triethylamine (1.8 cm3 12.62 mmol) at 0 8C under argon was added 1.82 g (12.1 mmol) of tert-butyldimethylsilyl chloride. The solution was stirred at this temperature for 30 min and then 5 h at room temp. The resultant suspension was diluted with ethyl acetate (100 cm3) and filtered over Celite. The solution was washed successively with 1 M HCl (100 cm3) and brine (3 × 100 cm3) dried (MgSO4) filtered and evaporated.The crude product (yellow solid) was purified by column chromatography on silica gel eluting with diethyl ether–hexane (1 1) to yield 2.40 g (79%) of monosilyl ether 4 and 82 mg (3%) of monosilyl ether 5 as white needles. Method B. To a stirred solution of the hydroxylactone 3 (1.02 g 5.86 mmol) DMAP (100 mg 0.82 mmol) and butylammonium iodide (108 mg 0.29 mmol) in dry DMF (9.6 cm3) and dry triethylamine (0.98 cm3 7.03 mmol) at room temp. under argon was added 1.01 g (6.73 mmol) of tert-butyldimethylsilyl chloride. The resultant solution was heated at 90 8C for 24 h and after cooling was diluted with ethyl acetate (100 cm3) and filtered over Celite. The solution was washed successively with 1 M HCl (100 cm3) and brine (3 × 100 cm3) dried (MgSO4) filtered and evaporated.The crude product was purified by column chromatography on silica gel eluting with diethyl ether– hexane (1 1 to 3 1) to yield 918 mg (54%) of monosilyl ether 5 and 505 mg (30%) of monosilyl ether 4 as white needles. (1R,3R,4S,5R)-5-tert-Butyldimethylsiloxy-1,4-dihydroxycyclohexane- 1,3-carbolactone 4. Mp 95–96 8C (from hexane) (Found C 54.12; H 8.45. C13H24SiO5 requires C 54.17; H 8.33%); [a]D 20 234 (c 1.1 in CH3OH); nmax/cm21 3300 (br OH) and 1780 (C]] O); dH(250 MHz; CDCl3) 4.85 (1 H dd J 6.0 and 4.7 3-H) 3.95 (1 H dd J 4.5 and 4.7 4-H) 3.86 (1 H ddd J 4.5 7.2 and 11.6 5-H) 3.00 (1 H s OH) 2.96 (1 H s OH) 2.59 (1 H d J 11.6 2ax-H) 2.28 (1 H ddd J 2.6 6.0 and 11.6 6eq- H) 1.89–2.06 (2 H m 6ax-H and 2eq-H) 0.88 [9 H s C(CH3)3] and 0.08 [6 H s Si(CH3)2]; dC(62 MHz; CDCl3) 178.1 76.3 71.7 67.0 65.6 40.1 36.4 25.6 17.9 24.7 and 25.0.(1S,3R,4R,5R)-4-tert-Butyldimethylsiloxy-1,5-dihydroxycyclohexane- 1,3-carbolactone 5. Mp 154–155 8C (from hexane) (Found C 54.21; H 8.39. C13H24O5Si requires C 54.17; H 8.33%); [a]D 20 224 (c 0.4 in CH3OH); nmax/cm21 3480 (OH) 3380 (OH) and 1800 (C]] O); dH(250 MHz; CDCl3) 4.65 (1 H dd J 6.0 and 4.2 3-H) 4.08 (1 H dd J 4.8 and 4.2 4-H) 3.80 (1 H dddd J 4.9 6.6 11.1 and 11.3 5-H) 2.99 (1 H s 1-OH) 2.50 (1 H d J 11.4 2ax-H) 2.29 (1 H ddd J 2.9 6.0 and 11.4 2eq-H) 2.17 (1 H ddd J 2.9 6.6 and 12.0 6eq-H) 2.09 (1 H d J 11.3 5-OH) 1.83 (1 H dd J 12.0 and 11.1 6ax-H) 0.92 [9 H s C(CH3)3] 0.15 (3 H s SiCH3) and 0.12 (3 H s SiCH3); dC(62 MHz; CDCl3) 177.9 (C) 76.3 (CH) 71.9 (C) 67.0 (CH) 65.8 (CH) 40.7 (CH2) 36.4 (CH2) 25.6 [C(CH3)3] 17.9 (C) 24.7 (SiCH3) and 25.0 (SiCH3).(1R,3R,4S)-4-tert-Butyldimethylsiloxy-1-hydroxy-5-oxocyclohexane- 1,3-carbolactone 6 To a stirred suspension of the alcohol 5 (232 mg 0.81 mmol) and 4 Å activated molecular sieves (300 mg) in dry dichloromethane (6 cm3) was added pyridinium dichromate (606 mg 1.61 mmol). The resultant suspension was stirred at room temp. for 2 h and then diluted with diethyl ether (60 cm3) and filtered over Celite. The solution was washed successively with HCl (5% 2 × 50 cm3) and brine (2 × 50 cm3) dried (MgSO4) filtered and evaporated. The product was recrystallised from hexane to afford 201 mg of the ketone 6 as white crystals (87%) mp 92–93 8C (Found C 54.46; H 7.84.C13H22SiO5 requires C 54.54; H 7.69%); [a]D 20 246 (c 0.4 in CH3OH); nmax/cm21 3350– 3500 (OH) 1810 (C]] O) and 1730 (C]] O); dH(62 MHz; CDCl3) 4.78 (1 H dd J 3.9 and 6.2 3-H) 4.05 (1 H ddd J 0.6 1.1 and 3.9 4-H) 3.10 (1 H d J 16.2 6ax-H) 2.95 (1 H s OH) 2.86 (1 H d J 12.1 2ax-H) 2.78 (1 H ddd J 1.1 3.1 and 16.2 6eq-H) 2.66 (1 H dddd J 0.6 3.1 6.2 and 12.1 2eq-H) 0.95 [9 H s C(CH3)3] 0.20 (3 H s SiCH3) and 0.16 (3 H s SiCH3); dC(250 MHz; CDCl3) 202.7 (C) 177.0 (C) 75.1 (CH) 71.4 (C) 70.6 (CH) 50.0 (CH2) 35.8 (CH2) 25.5 [C(CH3)3] 16.0 (C) 24.7 (SiCH3) and 25.3 (SiCH3); m/z (FAB+ve) 287 (MH+) (Found MH+ 287.1328. C13H23SiO5 requires M 287.1315). (1S,3R,4S,6R)-6-Bromo-4-tert-butyldimethylsiloxy-1-hydroxy- 5-oxocyclohexane-1,3-carbolactone 7 To a stirred solution of the ketone 6 (328 mg 1.15 mmol) in dry diethyl ether (30 cm3) under argon was added freshly made dioxane dibromide10 (313 mg 1.26 mmol).The red solution was stirred at room temp. until decoloration (2 h) diluted with diethyl ether (30 cm3) and washed successively with aqueous sodium metabisulfite (5% 30 cm3) aqueous sodium hydrogen carbonate (5% 30 cm3) and water (30 cm3). The organic layer was dried (MgSO4) filtered and evaporated. The product was recrystallised from hexane to afford the bromo ketone 7 as white needles (371 mg 89%) mp 124–125 8C (Found C 42.68; H 5.78. C13H21BrSiO5 requires C 42.74; H 5.75%); [a]D 20 2203 (c 0.4 in CH3OH); nmax/cm21 3540 (OH) 1820 (C]] O) and 1725 (C]] O); lmax(EtOH)/nm 238 and 339 (e/dm3 mol21 cm21 832 and 117); dH(250 MHz; CDCl3) 4.79 (1 H dd J 4.1 and 6.3 3-H) 4.35 (1 H dd J 1.2 and 2.5 6-H) 4.19 (1 H ddd J 0.9 1.2 and 4.1 4-H) 3.78 (1 H s OH) 3.33 (1 H d J 12.7 2ax-H) 2.55 (1 H dddd J 0.9 2.5 6.3 and 12.7 2eq-H) 0.95 [9 H s C(CH3)3] 0.26 (3 H s SiCH3) and 0.19 (3 H s SiCH3); dC(100 MHz; CDCl3) 198.3 (C) 172.8 (C) 76.4 (CH) 74.7 (C) 74.0 (CH) 71.0 (CH) 51.9 (CH) 32.7 (CH2) 25.3 [C(CH3)3] 17.9 (C) 25.3 (SiCH3) and 25.5 (SiCH3); m/z (FAB+ve) 365 (MH+) (Found MH+ 365.0420.C13H22BrSiO5 requires M 365.0420). (1S,2R,4S,5R)-2-Bromo-1,4,5-trihydroxy-3-oxocyclohexanecarboxylic acid [(2R)-2-bromodehydroquinic acid] 8 To a solution of the bromo ketone 7 (400 mg 1.10 mmol) in acetic acid (4 cm3) was added water (1 cm3) and the solution stirred at 40 8C for 72 h. The solution was lyophilised and the residue partitioned between ethyl acetate (25 cm3) and water (25 cm3).The aqueous phase was washed with ethyl acetate (25 cm3) and lyophilised to give the crude product. Recrystallisation 628 J. Chem. Soc. Perkin Trans. 1 1997 from ethyl acetate–hexane (50 50) yielded 2-bromodehydroquinic acid 8 (280 mg 95%) mp 112–114 8C (decomp.) (Found C 31.39; H 3.31. C7H9BrO6 requires C 31.23; H 3.35%); [a]D 20 236 (c 1.1 in CH3OH); nmax/cm21 3420 (OH) 3280 (OH) 1740 (C]] O) and 1700 (C]] O); dH(250 MHz; [2H6]acetone) 5.55 (1 H d J 0.9 2-H) 4.80 (3 H br s OH) 4.40 (1 H dd J 0.9 and 9.2 4-H) 3.96 (1 H ddd J 5.6 9.2 and 10.8 5-H) and 2.38–2.48 (2 H m 6-H); dC(62 MHz; [2H6]acetone) 197.8 (CH) 173.1 (C) 81.9 (CH) 77.9 (CH) 72.3 (CH) 61.7 (CH) and 40.9 (CH2); m/z (CI NH4 +) 268 266 252 250 188 and 172. (1S,3R,4S,6R)-6-Fluoro-4-(tert-butyldimethylsiloxy)-1- hydroxy-5-oxocyclohexane-1,3-carbolactone 9 To a stirred solution of the ketone 6 (47 mg 0.16 mmol) in dry toluene (1.2 cm3) under argon was added successively dry triethylamine (100 µl 0.74 mmol) and then trimethylsilyl trifluoromethanesulfonate (95 µl 0.49 mmol).The resultant mixture was refluxed for 2 h. After cooling at room temp. hexane was added (10 cm3) and the organic layer was washed with aqueous sodium hydrogen carbonate dried (MgSO4) filtered and evaporated. To the crude product dissolved in 1.6 cm3 of dry DMF under argon was added 58 mg (0.16 mmol) of Selectfluor‚ and the resultant mixture was stirred for 8 h. The reaction mixture was extracted with diethyl ether (3 × 10 cm3) dried (MgSO4) and evaporated to give a pale yellow solid. Recrystallisation from hexane yielded the protected fluoro ketone as white needles (40 mg 89%) [a]D 20 249 (c 0.5 in CH3OH); nmax(KBr)/cm21 3430 (OH) 1812 (C]] O) and 1753 (C]] O); dH(400 MHz; CDCl3) 5.21 (1 H d JH–F 48.4 6-H) 4.67 (1 H dd J 6.2 and 4.4) 4.25 (1 H dt J 1.5 and 4.2) 2.91 (1 H d J 12.9) 2.76 (2 H m) 0.87 [9 H s C(CH3)3] 0.14 (3 H s SiCH3) and 0.10 (3 H s SiCH3); dF(250 MHz; CDCl3) 2205 (1 F ddd JH–F 49 4 and 3); dC(100 MHz; CDCl3) 197.2 (C JC–F 13.0) 172.4 (C) 96.7 (CH JC–F 204.7) 74.6 (C JC–F 18.0) 73.8 (CH) 73.1 (CH) 34.0 (CH2) 25.4 [C(CH3)3] 17.9 (C) 25.0 (SiCH3) and 25.2 (SiCH3); m/z (FAB+ve) 305 (MH+) and 287 (MH+ 2 F) (Found MH+ 305.1221.C13H22SiO5F requires M 305.1209). (1S,3R,4S,6R)-2-Fluoro-1,4,5-trihydroxy-3-oxocyclohexanecarboxylic acid [(2R)-2-fluorodehydroquinic acid] 10 A stirred solution of the protected fluoro ketone 9 (25 mg 82.24 nmol) in 2 cm3 of a solution acetic acid–water (4 1) was heated at 50 8C for 48 h.The solvent was removed and the crude product was partitioned in 10 cm3 of ethyl acetate–water (1 1). The aqueous layer was washed with ethyl acetate (3 × 10 cm3) and then lyophilised. The crude product was purified by HPLC using the Organic Acids column eluting with aqueous formic acid (50 mM) to yield 2-fluorodehydroquinic acid 11 (15 mg 90%) as a white hygroscopic solid tr 15 min (flow rate 1.2 cm3 min21); lmax(H2O)/nm 191 and 270; [a]D 20 230 (c 0.1 in water); nmax(KBr)/cm21 3420 (OH) 1750 (C]] O) and 1720 (C]] O); dH(500 MHz; D2O) 5.64 (1 H dd JH–F 46.3 and 0.8 2-H) 4.34 (1 H d J 9.4 4-H) 3.85 (1 H m 5-H) and 2.30–2.18 (2 H m 6- H); dF(235 MHz; CDCl3) 2207 (1 F dd JH–F 47 and 8); dC(100 MHz; D2O) 206.1 (C JC–F 14) 178.3 (C) 96.9 (CH JC–F 195) 81.7 (CH) 77.8 (C) 74.0 (CH) and 39.3 (CH2 JC–F 6); m/z (ESI) 231 (MNa+) (Found MNa+ 231.0278.C7H9O6FNa requires M 231.0278). Acknowledgements We thank the Royal Society for an Endeavour Research Fellowship for M. K. M. and the BBSRC for postdoctoral funding for C. G. B. We thank Joanna Harris for NOE studies and Dr Finian Leeper for helpful discussions. References 1 R. Bentley CRC Crit. Rev. Biochem. 1990 25 307. 2 M. R. Boocock and J. R. Coggins FEBS Lett. 1983 154 127. 3 G. M. Davies K. J. Barrettbee D. A. Jude M. Lehan W. W. Nichols P. E. Pinder J. L. Thain W. J. Watkins and R. G. Wilson Antimicrob. Agents Chemother. 1994 38 403. 4 R. H. Rich B. M. Lawrence and P.A. Bartlett J. Org. Chem. 1994 59 693. 5 R. H. Rich and P. A. Bartlett J. Org. Chem. 1996 61 3916. 6 M. Adlersberg W. E. Bondinell and D. B. Sprinson J. Am. Chem. Soc. 1973 95 887. 7 D. Lesuisse and G. A. Berchtold J. Org. Chem. 1985 50 888. 8 L. Panizzi M. L. Scarpati and R. Scarpati Gazz. Chim. Ital. 1954 84 806. 9 G. S. Lal J. Org. Chem. 1993 58 2791. 10 P. Duhamel L. Duhamel and J. Y. Valnot Bull. Soc. Chim. Fr. 1973 1465. Paper 6/06104D Received 5th September 1996 Accepted 23rd October 1996 J. Chem. Soc. Perkin Trans. 1 1997 625 Synthesis of (2R)-2-bromodehydroquinic acid and (2R)-2-fluorodehydroquinic acid † Michael K. Manthey,‡ Concepción González-Bello § and Chris Abell * Cambridge Centre for Molecular Recognition University Chemical Laboratory Lensfield Road Cambridge CB2 1EW UK (2R)-2-Bromodehydroquinic acid and (2R)-2-fluorodehydroquinic acid † have each been synthesised in six steps from quinic acid via the common intermediate 6.The syntheses exploit the selective protection of the 4-hydroxy group of the quinic acid lactone 3 with tert-butyldimethylsilyl chloride. The shikimate pathway to the aromatic amino acids 1 is a target for herbicides and antimicrobial agents. The broad spectrum post-emergence herbicide glyphosate acts by inhibiting 5- enolpyruvyl shikimate 3-phosphate (EPSP) synthase,2 and recently the antimicrobial action has been demonstrated for (6S)-6-fluoroshikimic acid.3 Interest in this pathway has resulted in the synthesis of many analogues of pathway intermediates especially derivatives of shikimic acid. We are interested in dehydroquinic acid analogues substituted at C-2 as potential inhibitors of 3-dehydroquinate dehydratase.Here we describe the synthesis of (2R)-2-bromodehydroquinic acid 8 and (2R)-2-fluorodehydroquinic acid 10.† These are the first syntheses of 2-substituted dehydroquinic acid derivatives. Bartlett and co-workers have recently reported the synthesis of the corresponding 2-bromoshikimic acid 4 and 2-fluoroshikimic acid.5 (2R)- and (2S)-2-Hydroxyquinic acids and (2R)-2-bromoquinic acid have also been synthesised.6 Quinic acid was used as an inexpensive chiral advanced intermediate. The required transformations are selective oxidation at C-3 and introduction of the halogenic substituent at C-2. However to achieve this it is necessary to protect the other functionality present in quinic acid (Scheme 1).The first step involves the quadruple protection of quinic acid 1 in the toluene-p-sulfonic acid catalysed reaction with benzaldehyde.7 Azeotropic removal of the water gave the benzylidene acetal 2 as a 2.2 1 mixture of diastereoisomers in 79% yield. The major isomer was isolated after recrystallisation from diethyl ether. The benzylidene centre was shown to have the Rconfiguration by observation of NOEs from H-4 and H-5 to the benzylidene hydrogen in the 1H NMR spectrum. The benzylidene protecting group was removed by catalytic hydrogenation over 10% palladium on charcoal to give quinic acid lactone 3 in 93% yield. It is possible to convert 1 directly into 3 8 but the two step procedure used has been found to be experimentally preferable. The selective protection of the C-4 hydroxy group of 3 was achieved using tert-butyldimethylsilyl (TBDMS) chloride.Reaction of 3 with TBDMS chloride in N,N-dimethylformamide (DMF) at 0 8C for 6 h gave a mixture of the monoprotected compounds 4 and 5 in a ratio of 97 3 (combined yield 82%). However if the reaction was carried out at 90 8C the selectivity was reversed and the product ratio was then 1 2 † IUPAC names (1S,2R,4S,5R)-2-bromo-1,4,5-trihydroxy-3-oxocyclohexanecarboxylic acid and (1S,2R,4S,5R)-2-fluoro-1,4,5-trihydroxy-3- oxocyclohexanecarboxylic acid respectively. ‡ Present address Department of Biochemistry The University of Sydney Sydney NSW 2006 Australia. § Present address Departamento de Química Orgánica Facultad de Ciencias Augas Férreas Polígono Fingoi 27002 Lugo Spain. in favour of the required C-4 silyl ether (combined yield 84%).Submission of the kinetic product 4 to the higher temperature conditions resulted in it being converted to a mixture of 4 and 5. The structure of 5 was assigned after careful NMR spectroscopic studies. The 1H NMR spectrum recorded under rigorously dry conditions showed an 11.3 Hz coupling between 5-H and a hydroxy proton. Furthermore NOE difference spectroscopy indicated significant enhancements of 3-H and 5-H and in the TBDMS protons upon irradiation of 4-H. Conversely irradiation of 5-H resulted in enhancement of 4-H 6eq-H and the C-5 hydroxy proton. Irradiation of 3-H resulted in enhancement of 4-H 2eq-H 2ax-H and the TBDMS protons. These observations and subsequent chemical transformations con- Scheme 1 Reagents conditions and yields (i) PhCHO 4-TsOH toluene reflux (74%); (ii) H2 [10%]Pd/C AcOH room temp.(94%); (iii) TBDMSCl DMAP Et3N Bu4NI 0 8C (79%); (iv) TBDMSCl DMAP Et3N Bu4NI 90 8C (54%); (v) PDC 4 Å molecular sieves CH2Cl2 room temp. (87%) 626 J. Chem. Soc. Perkin Trans. 1 1997 firmed the location of the silyl group in 5 and hence the corresponding location in 4. The secondary hydroxy group in 5 was readily oxidised using either pyridinium chlorochromate (PCC) tetrapropylammonium perruthenate–N-methylmorpholine N-oxide (TPAP– MNO) or pyridinium dichromate (PDC) in the presence of 4 Å activated molecular sieves. The latter reaction proceeded in the highest yield (87%) to give the ketone 6. This compound is acidsensitive and so was purified by recrystallisation from hexane. Ketone 6 is the key intermediate in the synthesis of both (2R)-2-bromodehydroquinic acid 8 and (2R)-2-fluorodehydroquinic acid 10 (Scheme 2).For the synthesis of (2R)-2- bromodehydroquinic acid the bromine is introduced stereoselectively using dioxane dibromide10 to afford the axiallybrominated derivative 7 (89%). In the NMR spectrum of 7 the axial bromine causes a downfield shift in the signal for the hydrogen 1,3-diaxial to it (2ax-H) from d 2.86 in 6 to d 3.33. The isolation of a single diastereoisomer of 7 is presumed to be due to preferential bromination on the side of the ketone 6 opposite to the bridging lactone group. The TBDMS protecting group of 7 was removed and the lactone opened by mild acid hydrolysis (HOAc–H2O–THF) at 40 8C to give the required (2R)-2-bromodehydroquinic acid 8 in 95% yield.The equatorial position of the bromine was confirmed by NMR spectroscopy. Irradiation of 2-H led to enhancement of the signals for 4-H (6%) and 6ax-H (4%). Correspondingly irradiation of 4-H enhanced the signals for 2-H (6%) and 6ax-H (3%). The configuration at C-2 (C-6 in compound 7) is unchanged in going from 7 to 8 it is simply the cleaving of the lactone which allows the ring to flip to the other chair conformation. (2R)-2-Fluorodehydroquinic acid 10 was synthesised from the protected ketone 6 in two steps. The silyl enol ether was made using trimethylsilyl trifluoromethanesulfonate and reacted directly with Selectfluor‚ 9 in DMF to give the protected fluoro ketone 9 in 89% yield. This was deprotected in aqueous Scheme 2 Reagents conditions and yields (i) Br2?dioxane Et2O room temp.(89%); (ii) AcOH THF H2O 40 8C (95%); (iii) (a) TMSOTf Et3N toluene reflux (b) Selectfluor‚ DMF room temp. (89%); (iv) AcOH H2O 50 8C (90%) acetic acid to give 10 (90%). The equatorial position of the fluorine was confirmed by NMR spectroscopy. The fluorine has a geminal coupling to 2-H of 47 Hz and a W-coupling to 6eq-H of 8 Hz. Irradiation of 2-H led to enhancement of the signals for 4-H (6%) and 6ax-H (4%). Correspondingly irradiation of 4-H enhanced the signals for 2-H (6%) and 6ax-H (3%). (2R)-2-Bromodehydroquinic acid and (2R)-2-fluorodehydroquinic acid are stable in either water or acetone at 4 8C. However upon heating to over 80 8C quantitative dehydrohalogenation and aromatisation yield 3,4,5-trihydroxybenzoic acid. The syntheses of (2R)-2-bromodehydroquinic acid 8 and (2R)-2-fluorodehydroquinic acid 10 are both short and highyielding especially in light of the problems encountered in the synthesis of the related 2-bromoshikimic acid 4 and 2-fluoroshikimic acid.5 Preliminary studies show that both 8 and 10 are inhibitors for dehydroquinate dehydratase the third enzyme on the shikimate pathway.Full details of these biological studies will be published elsewhere. Experimental General NMR Spectra were recorded on either a Bruker WM-250 WM-400 DPX-250 or DPX-500 NMR spectrometer in deuteriated solvents with tetramethylsilane as an internal standard. J Values are given in Hz. Melting points were determined on a Buchi 510 or Reichert melting points apparatus and are uncorrected. IR Spectra were recorded on a Perkin-Elmer 1310 infrared spectrometer or a 1710 Fourier Transform spectrometer as Nujol mulls unless otherwise indicated.Mass spectra were recorded on a Kratos MS890 double-focussing magnetic sector apparatus (for EI CI and FAB). Optical rotations were measured on an AA-10 automatic polarimeter (Optical Activity Ltd.); [a]D values are given in 1021 deg cm2 g21. All organic solvents were freshly distilled prior to use. Dichloromethane triethylamine toluene and hexane were dried over calcium hydride. Methanol was dried over potassium carbonate. Diethyl ether was dried over lithium aluminium hydride. Analytical thin layer chromatography was carried out on commercial Kieselgel 60 0.25 mm silica plates. Spots were visualised by UV absorbance at 254 nm iodine potasium permanganate(VII) or cerium molybdate solution.Flash chromatography was carried out using 230–400 mesh Kieselgel 60 silica. The carboxylic acids were purified by HPLC on a preparative (300 mm × 16 mm) Bio-Rad Aminex Ion Exclusion HPX-87H Organic Acids column eluting with aqueous formic acid (50 mM) at a flow rate of 1.2 cm3 min21 with the UV detector set at 277 nm. (1S,3R,4R,5R)-4,5-Benzylidenedioxy-1-hydroxycyclohexane- 1,3-carbolactone 2 A mixture of (2)-quinic acid 1 (4.94 g 25.7 mmol) distilled benzaldehyde (3.9 cm3 38.6 mmol) and toluene-p-sulfonic acid (253 mg 1.3 mmol) was heated at reflux in toluene (50 cm3) in an apparatus fitted with a Dean–Stark trap for 22 h. The solution was allowed to cool and the toluene evaporated at reduced pressure. The oily residue was taken up in diethyl ether and decanted from the solid. The crude mixture was purified by column chromatography on silica gel eluting with ethyl acetate– light petroleum (bp 40–60 8C) (1 1) to give the benzylidene carbolactones 2 (5.31 g 79%) as a mixture of diastereoisomers at the benzylic carbon in a ratio of 2.2 1.On cooling the viscous oil crystallised. Recrystallisation from diethyl ether gave the major diastereoisomer (with the R configuration at the benzylic centre) of carbolactone 2 as white needles mp 100–101 8C (lit.,7 95 8C); RF 0.46 [ethyl acetate–light petroleum (bp 40–60 8C) 1 1] (Found C 63.9; H 5.4. C14H14O5 requires C 64.1; H 5.4%); nmax(CH2Cl2)/cm21 3540 (free OH) 3420 (H-bonded OH) 1800 (C]] O) and 1470 (Ar C–C); dH(250 MHz; CDCl3) 7.51–7.36 (5 H m Ph) 5.75 (1 H s PhCHO2) 4.81 (1 H dd J J. Chem. Soc. Perkin Trans.1 1997 627 6.1 and 2.1 3-H) 4.52 (1 H td J 7.0 and 2.7 5-H) 4.37 (1 H dt J 7.0 and 2.1 4-H) 2.91 (1 H br s OH) 2.78 (1 H d J 11.9 2ax-H) 2.46 (1 H ddd J 15.1 7.0 and 2.1 6eq-H) 2.36 (1 H dd J 15.1 and 2.7 6ax-H) and 2.34 (1 H ddt J 11.9 6.1 and 2.1 2eq-H); dC(62 MHz; CDCl3) 178.9 135.4 129.9 128.6 126.6 103.7 75.5 72.9 72.7 71.4 37.7 and 34.4; m/z (EI+) 262 (M+) 261 [(M 2 H)+] and 105 [(PhCO)+] (Found M+ 262.0820. C14H14O5 requires M 262.0841). (1S,3R,4R,5R)-1,4,5-Trihydroxycyclohexane-1,3-carbolactone 3 To 500 mg of palladium on charcoal (10%) under a hydrogen atmosphere was added glacial acetic acid (10 cm3). After 10 min a solution of the acetal 2 (5 g 19.0 mol) in glacial acetic acid (40 cm3) was added. The system was evacuated and kept under a hydrogen atmosphere until reduction was complete as judged by TLC (48 h).The hydrogen was evacuated the suspension filtered over Celite and washed with acetic acid (50 cm3) and methanol (50 cm3). The solvent was removed under reduced pressure and the product was recrystallised from acetic acid to afford 3.09 g (94%) of the hydroxylactone 3 as white prisms mp 184–185 8C (lit.,8 185–189 8C); nmax/cm21 3000–3560 (OH) and 1780 (C]] O); dH(250 MHz; CD3OD) 4.91 (3 H br s OH) 4.75 (1 H dd J 4.9 and 6.0 3-H) 4.02 (1 H dd J 4.5 and 4.9 4-H) 3.74 (1 H ddd J 4.5 6.6 and 11.3 5-H) 2.51 (1 H d J 11.5 2ax-H) 2.26 (1 H ddd J 2.9 6.0 and 11.5 2eq-H) 2.07 (1 H ddd J 6.6 2.9 and 11.6 6eq-H) and 1.91 (1 H dd J 11.3 and 11.6 6ax-H); dC(62 MHz; CD3OD) 179.5 77.6 73.1 67.3 66.8 40.0 and 37.8. Selective monosilylation of the trihydroxylactone 3 Method A.To a stirred solution of the hydroxylactone 3 (1.83 g 10.52 mmol) 4-dimethylaminopyridine (DMAP) (180 mg 1.47 mmol) and butylammonium iodide (194 mg 0.53 mmol) in dry DMF (17 cm3) and dry triethylamine (1.8 cm3 12.62 mmol) at 0 8C under argon was added 1.82 g (12.1 mmol) of tert-butyldimethylsilyl chloride. The solution was stirred at this temperature for 30 min and then 5 h at room temp. The resultant suspension was diluted with ethyl acetate (100 cm3) and filtered over Celite. The solution was washed successively with 1 M HCl (100 cm3) and brine (3 × 100 cm3) dried (MgSO4) filtered and evaporated. The crude product (yellow solid) was purified by column chromatography on silica gel eluting with diethyl ether–hexane (1 1) to yield 2.40 g (79%) of monosilyl ether 4 and 82 mg (3%) of monosilyl ether 5 as white needles.Method B. To a stirred solution of the hydroxylactone 3 (1.02 g 5.86 mmol) DMAP (100 mg 0.82 mmol) and butylammonium iodide (108 mg 0.29 mmol) in dry DMF (9.6 cm3) and dry triethylamine (0.98 cm3 7.03 mmol) at room temp. under argon was added 1.01 g (6.73 mmol) of tert-butyldimethylsilyl chloride. The resultant solution was heated at 90 8C for 24 h and after cooling was diluted with ethyl acetate (100 cm3) and filtered over Celite. The solution was washed successively with 1 M HCl (100 cm3) and brine (3 × 100 cm3) dried (MgSO4) filtered and evaporated. The crude product was purified by column chromatography on silica gel eluting with diethyl ether– hexane (1 1 to 3 1) to yield 918 mg (54%) of monosilyl ether 5 and 505 mg (30%) of monosilyl ether 4 as white needles.(1R,3R,4S,5R)-5-tert-Butyldimethylsiloxy-1,4-dihydroxycyclohexane- 1,3-carbolactone 4. Mp 95–96 8C (from hexane) (Found C 54.12; H 8.45. C13H24SiO5 requires C 54.17; H 8.33%); [a]D 20 234 (c 1.1 in CH3OH); nmax/cm21 3300 (br OH) and 1780 (C]] O); dH(250 MHz; CDCl3) 4.85 (1 H dd J 6.0 and 4.7 3-H) 3.95 (1 H dd J 4.5 and 4.7 4-H) 3.86 (1 H ddd J 4.5 7.2 and 11.6 5-H) 3.00 (1 H s OH) 2.96 (1 H s OH) 2.59 (1 H d J 11.6 2ax-H) 2.28 (1 H ddd J 2.6 6.0 and 11.6 6eq- H) 1.89–2.06 (2 H m 6ax-H and 2eq-H) 0.88 [9 H s C(CH3)3] and 0.08 [6 H s Si(CH3)2]; dC(62 MHz; CDCl3) 178.1 76.3 71.7 67.0 65.6 40.1 36.4 25.6 17.9 24.7 and 25.0. (1S,3R,4R,5R)-4-tert-Butyldimethylsiloxy-1,5-dihydroxycyclohexane- 1,3-carbolactone 5. Mp 154–155 8C (from hexane) (Found C 54.21; H 8.39.C13H24O5Si requires C 54.17; H 8.33%); [a]D 20 224 (c 0.4 in CH3OH); nmax/cm21 3480 (OH) 3380 (OH) and 1800 (C]] O); dH(250 MHz; CDCl3) 4.65 (1 H dd J 6.0 and 4.2 3-H) 4.08 (1 H dd J 4.8 and 4.2 4-H) 3.80 (1 H dddd J 4.9 6.6 11.1 and 11.3 5-H) 2.99 (1 H s 1-OH) 2.50 (1 H d J 11.4 2ax-H) 2.29 (1 H ddd J 2.9 6.0 and 11.4 2eq-H) 2.17 (1 H ddd J 2.9 6.6 and 12.0 6eq-H) 2.09 (1 H d J 11.3 5-OH) 1.83 (1 H dd J 12.0 and 11.1 6ax-H) 0.92 [9 H s C(CH3)3] 0.15 (3 H s SiCH3) and 0.12 (3 H s SiCH3); dC(62 MHz; CDCl3) 177.9 (C) 76.3 (CH) 71.9 (C) 67.0 (CH) 65.8 (CH) 40.7 (CH2) 36.4 (CH2) 25.6 [C(CH3)3] 17.9 (C) 24.7 (SiCH3) and 25.0 (SiCH3). (1R,3R,4S)-4-tert-Butyldimethylsiloxy-1-hydroxy-5-oxocyclohexane- 1,3-carbolactone 6 To a stirred suspension of the alcohol 5 (232 mg 0.81 mmol) and 4 Å activated molecular sieves (300 mg) in dry dichloromethane (6 cm3) was added pyridinium dichromate (606 mg 1.61 mmol).The resultant suspension was stirred at room temp. for 2 h and then diluted with diethyl ether (60 cm3) and filtered over Celite. The solution was washed successively with HCl (5% 2 × 50 cm3) and brine (2 × 50 cm3) dried (MgSO4) filtered and evaporated. The product was recrystallised from hexane to afford 201 mg of the ketone 6 as white crystals (87%) mp 92–93 8C (Found C 54.46; H 7.84. C13H22SiO5 requires C 54.54; H 7.69%); [a]D 20 246 (c 0.4 in CH3OH); nmax/cm21 3350– 3500 (OH) 1810 (C]] O) and 1730 (C]] O); dH(62 MHz; CDCl3) 4.78 (1 H dd J 3.9 and 6.2 3-H) 4.05 (1 H ddd J 0.6 1.1 and 3.9 4-H) 3.10 (1 H d J 16.2 6ax-H) 2.95 (1 H s OH) 2.86 (1 H d J 12.1 2ax-H) 2.78 (1 H ddd J 1.1 3.1 and 16.2 6eq-H) 2.66 (1 H dddd J 0.6 3.1 6.2 and 12.1 2eq-H) 0.95 [9 H s C(CH3)3] 0.20 (3 H s SiCH3) and 0.16 (3 H s SiCH3); dC(250 MHz; CDCl3) 202.7 (C) 177.0 (C) 75.1 (CH) 71.4 (C) 70.6 (CH) 50.0 (CH2) 35.8 (CH2) 25.5 [C(CH3)3] 16.0 (C) 24.7 (SiCH3) and 25.3 (SiCH3); m/z (FAB+ve) 287 (MH+) (Found MH+ 287.1328.C13H23SiO5 requires M 287.1315). (1S,3R,4S,6R)-6-Bromo-4-tert-butyldimethylsiloxy-1-hydroxy- 5-oxocyclohexane-1,3-carbolactone 7 To a stirred solution of the ketone 6 (328 mg 1.15 mmol) in dry diethyl ether (30 cm3) under argon was added freshly made dioxane dibromide10 (313 mg 1.26 mmol). The red solution was stirred at room temp. until decoloration (2 h) diluted with diethyl ether (30 cm3) and washed successively with aqueous sodium metabisulfite (5% 30 cm3) aqueous sodium hydrogen carbonate (5% 30 cm3) and water (30 cm3).The organic layer was dried (MgSO4) filtered and evaporated. The product was recrystallised from hexane to afford the bromo ketone 7 as white needles (371 mg 89%) mp 124–125 8C (Found C 42.68; H 5.78. C13H21BrSiO5 requires C 42.74; H 5.75%); [a]D 20 2203 (c 0.4 in CH3OH); nmax/cm21 3540 (OH) 1820 (C]] O) and 1725 (C]] O); lmax(EtOH)/nm 238 and 339 (e/dm3 mol21 cm21 832 and 117); dH(250 MHz; CDCl3) 4.79 (1 H dd J 4.1 and 6.3 3-H) 4.35 (1 H dd J 1.2 and 2.5 6-H) 4.19 (1 H ddd J 0.9 1.2 and 4.1 4-H) 3.78 (1 H s OH) 3.33 (1 H d J 12.7 2ax-H) 2.55 (1 H dddd J 0.9 2.5 6.3 and 12.7 2eq-H) 0.95 [9 H s C(CH3)3] 0.26 (3 H s SiCH3) and 0.19 (3 H s SiCH3); dC(100 MHz; CDCl3) 198.3 (C) 172.8 (C) 76.4 (CH) 74.7 (C) 74.0 (CH) 71.0 (CH) 51.9 (CH) 32.7 (CH2) 25.3 [C(CH3)3] 17.9 (C) 25.3 (SiCH3) and 25.5 (SiCH3); m/z (FAB+ve) 365 (MH+) (Found MH+ 365.0420.C13H22BrSiO5 requires M 365.0420). (1S,2R,4S,5R)-2-Bromo-1,4,5-trihydroxy-3-oxocyclohexanecarboxylic acid [(2R)-2-bromodehydroquinic acid] 8 To a solution of the bromo ketone 7 (400 mg 1.10 mmol) in acetic acid (4 cm3) was added water (1 cm3) and the solution stirred at 40 8C for 72 h. The solution was lyophilised and the residue partitioned between ethyl acetate (25 cm3) and water (25 cm3). The aqueous phase was washed with ethyl acetate (25 cm3) and lyophilised to give the crude product. Recrystallisation 628 J. Chem. Soc. Perkin Trans. 1 1997 from ethyl acetate–hexane (50 50) yielded 2-bromodehydroquinic acid 8 (280 mg 95%) mp 112–114 8C (decomp.) (Found C 31.39; H 3.31.C7H9BrO6 requires C 31.23; H 3.35%); [a]D 20 236 (c 1.1 in CH3OH); nmax/cm21 3420 (OH) 3280 (OH) 1740 (C]] O) and 1700 (C]] O); dH(250 MHz; [2H6]acetone) 5.55 (1 H d J 0.9 2-H) 4.80 (3 H br s OH) 4.40 (1 H dd J 0.9 and 9.2 4-H) 3.96 (1 H ddd J 5.6 9.2 and 10.8 5-H) and 2.38–2.48 (2 H m 6-H); dC(62 MHz; [2H6]acetone) 197.8 (CH) 173.1 (C) 81.9 (CH) 77.9 (CH) 72.3 (CH) 61.7 (CH) and 40.9 (CH2); m/z (CI NH4 +) 268 266 252 250 188 and 172. (1S,3R,4S,6R)-6-Fluoro-4-(tert-butyldimethylsiloxy)-1- hydroxy-5-oxocyclohexane-1,3-carbolactone 9 To a stirred solution of the ketone 6 (47 mg 0.16 mmol) in dry toluene (1.2 cm3) under argon was added successively dry triethylamine (100 µl 0.74 mmol) and then trimethylsilyl trifluoromethanesulfonate (95 µl 0.49 mmol).The resultant mixture was refluxed for 2 h. After cooling at room temp. hexane was added (10 cm3) and the organic layer was washed with aqueous sodium hydrogen carbonate dried (MgSO4) filtered and evaporated. To the crude product dissolved in 1.6 cm3 of dry DMF under argon was added 58 mg (0.16 mmol) of Selectfluor‚ and the resultant mixture was stirred for 8 h. The reaction mixture was extracted with diethyl ether (3 × 10 cm3) dried (MgSO4) and evaporated to give a pale yellow solid. Recrystallisation from hexane yielded the protected fluoro ketone as white needles (40 mg 89%) [a]D 20 249 (c 0.5 in CH3OH); nmax(KBr)/cm21 3430 (OH) 1812 (C]] O) and 1753 (C]] O); dH(400 MHz; CDCl3) 5.21 (1 H d JH–F 48.4 6-H) 4.67 (1 H dd J 6.2 and 4.4) 4.25 (1 H dt J 1.5 and 4.2) 2.91 (1 H d J 12.9) 2.76 (2 H m) 0.87 [9 H s C(CH3)3] 0.14 (3 H s SiCH3) and 0.10 (3 H s SiCH3); dF(250 MHz; CDCl3) 2205 (1 F ddd JH–F 49 4 and 3); dC(100 MHz; CDCl3) 197.2 (C JC–F 13.0) 172.4 (C) 96.7 (CH JC–F 204.7) 74.6 (C JC–F 18.0) 73.8 (CH) 73.1 (CH) 34.0 (CH2) 25.4 [C(CH3)3] 17.9 (C) 25.0 (SiCH3) and 25.2 (SiCH3); m/z (FAB+ve) 305 (MH+) and 287 (MH+ 2 F) (Found MH+ 305.1221.C13H22SiO5F requires M 305.1209). (1S,3R,4S,6R)-2-Fluoro-1,4,5-trihydroxy-3-oxocyclohexanecarboxylic acid [(2R)-2-fluorodehydroquinic acid] 10 A stirred solution of the protected fluoro ketone 9 (25 mg 82.24 nmol) in 2 cm3 of a solution acetic acid–water (4 1) was heated at 50 8C for 48 h. The solvent was removed and the crude product was partitioned in 10 cm3 of ethyl acetate–water (1 1). The aqueous layer was washed with ethyl acetate (3 × 10 cm3) and then lyophilised.The crude product was purified by HPLC using the Organic Acids column eluting with aqueous formic acid (50 mM) to yield 2-fluorodehydroquinic acid 11 (15 mg 90%) as a white hygroscopic solid tr 15 min (flow rate 1.2 cm3 min21); lmax(H2O)/nm 191 and 270; [a]D 20 230 (c 0.1 in water); nmax(KBr)/cm21 3420 (OH) 1750 (C]] O) and 1720 (C]] O); dH(500 MHz; D2O) 5.64 (1 H dd JH–F 46.3 and 0.8 2-H) 4.34 (1 H d J 9.4 4-H) 3.85 (1 H m 5-H) and 2.30–2.18 (2 H m 6- H); dF(235 MHz; CDCl3) 2207 (1 F dd JH–F 47 and 8); dC(100 MHz; D2O) 206.1 (C JC–F 14) 178.3 (C) 96.9 (CH JC–F 195) 81.7 (CH) 77.8 (C) 74.0 (CH) and 39.3 (CH2 JC–F 6); m/z (ESI) 231 (MNa+) (Found MNa+ 231.0278. C7H9O6FNa requires M 231.0278). Acknowledgements We thank the Royal Society for an Endeavour Research Fellowship for M.K. M. and the BBSRC for postdoctoral funding for C. G. B. We thank Joanna Harris for NOE studies and Dr Finian Leeper for helpful discussions. References 1 R. Bentley CRC Crit. Rev. Biochem. 1990 25 307. 2 M. R. Boocock and J. R. Coggins FEBS Lett. 1983 154 127. 3 G. M. Davies K. J. Barrettbee D. A. Jude M. Lehan W. W. Nichols P. E. Pinder J. L. Thain W. J. Watkins and R. G. Wilson Antimicrob. Agents Chemother. 1994 38 403. 4 R. H. Rich B. M. Lawrence and P. A. Bartlett J. Org. Chem. 1994 59 693. 5 R. H. Rich and P. A. Bartlett J. Org. Chem. 1996 61 3916. 6 M. Adlersberg W. E. Bondinell and D. B. Sprinson J. Am. Chem. Soc. 1973 95 887. 7 D. Lesuisse and G. A. Berchtold J. Org. Chem. 1985 50 888. 8 L. Panizzi M. L. Scarpati and R.Scarpati Gazz. Chim. Ital. 1954 84 806. 9 G. S. Lal J. Org. Chem. 1993 58 2791. 10 P. Duhamel L. Duhamel and J. Y. Valnot Bull. Soc. Chim. Fr. 1973 1465. Paper 6/06104D Received 5th September 1996 Accepted 23rd October 1996 J. Chem. Soc. Perkin Trans. 1 1997 625 Synthesis of (2R)-2-bromodehydroquinic acid and (2R)-2-fluorodehydroquinic acid † Michael K. Manthey,‡ Concepción González-Bello § and Chris Abell * Cambridge Centre for Molecular Recognition University Chemical Laboratory Lensfield Road Cambridge CB2 1EW UK (2R)-2-Bromodehydroquinic acid and (2R)-2-fluorodehydroquinic acid † have each been synthesised in six steps from quinic acid via the common intermediate 6. The syntheses exploit the selective protection of the 4-hydroxy group of the quinic acid lactone 3 with tert-butyldimethylsilyl chloride.The shikimate pathway to the aromatic amino acids 1 is a target for herbicides and antimicrobial agents. The broad spectrum post-emergence herbicide glyphosate acts by inhibiting 5- enolpyruvyl shikimate 3-phosphate (EPSP) synthase,2 and recently the antimicrobial action has been demonstrated for (6S)-6-fluoroshikimic acid.3 Interest in this pathway has resulted in the synthesis of many analogues of pathway intermediates especially derivatives of shikimic acid. We are interested in dehydroquinic acid analogues substituted at C-2 as potential inhibitors of 3-dehydroquinate dehydratase. Here we describe the synthesis of (2R)-2-bromodehydroquinic acid 8 and (2R)-2-fluorodehydroquinic acid 10.† These are the first syntheses of 2-substituted dehydroquinic acid derivatives.Bartlett and co-workers have recently reported the synthesis of the corresponding 2-bromoshikimic acid 4 and 2-fluoroshikimic acid.5 (2R)- and (2S)-2-Hydroxyquinic acids and (2R)-2-bromoquinic acid have also been synthesised.6 Quinic acid was used as an inexpensive chiral advanced intermediate. The required transformations are selective oxidation at C-3 and introduction of the halogenic substituent at C-2. However to achieve this it is necessary to protect the other functionality present in quinic acid (Scheme 1). The first step involves the quadruple protection of quinic acid 1 in the toluene-p-sulfonic acid catalysed reaction with benzaldehyde.7 Azeotropic removal of the water gave the benzylidene acetal 2 as a 2.2 1 mixture of diastereoisomers in 79% yield.The major isomer was isolated after recrystallisation from diethyl ether. The benzylidene centre was shown to have the Rconfiguration by observation of NOEs from H-4 and H-5 to the benzylidene hydrogen in the 1H NMR spectrum. The benzylidene protecting group was removed by catalytic hydrogenation over 10% palladium on charcoal to give quinic acid lactone 3 in 93% yield. It is possible to convert 1 directly into 3 8 but the two step procedure used has been found to be experimentally preferable. The selective protection of the C-4 hydroxy group of 3 was achieved using tert-butyldimethylsilyl (TBDMS) chloride. Reaction of 3 with TBDMS chloride in N,N-dimethylformamide (DMF) at 0 8C for 6 h gave a mixture of the monoprotected compounds 4 and 5 in a ratio of 97 3 (combined yield 82%).However if the reaction was carried out at 90 8C the selectivity was reversed and the product ratio was then 1 2 † IUPAC names (1S,2R,4S,5R)-2-bromo-1,4,5-trihydroxy-3-oxocyclohexanecarboxylic acid and (1S,2R,4S,5R)-2-fluoro-1,4,5-trihydroxy-3- oxocyclohexanecarboxylic acid respectively. ‡ Present address Department of Biochemistry The University of Sydney Sydney NSW 2006 Australia. § Present address Departamento de Química Orgánica Facultad de Ciencias Augas Férreas Polígono Fingoi 27002 Lugo Spain. in favour of the required C-4 silyl ether (combined yield 84%). Submission of the kinetic product 4 to the higher temperature conditions resulted in it being converted to a mixture of 4 and 5. The structure of 5 was assigned after careful NMR spectroscopic studies. The 1H NMR spectrum recorded under rigorously dry conditions showed an 11.3 Hz coupling between 5-H and a hydroxy proton.Furthermore NOE difference spectroscopy indicated significant enhancements of 3-H and 5-H and in the TBDMS protons upon irradiation of 4-H. Conversely irradiation of 5-H resulted in enhancement of 4-H 6eq-H and the C-5 hydroxy proton. Irradiation of 3-H resulted in enhancement of 4-H 2eq-H 2ax-H and the TBDMS protons. These observations and subsequent chemical transformations con- Scheme 1 Reagents conditions and yields (i) PhCHO 4-TsOH toluene reflux (74%); (ii) H2 [10%]Pd/C AcOH room temp. (94%); (iii) TBDMSCl DMAP Et3N Bu4NI 0 8C (79%); (iv) TBDMSCl DMAP Et3N Bu4NI 90 8C (54%); (v) PDC 4 Å molecular sieves CH2Cl2 room temp. (87%) 626 J. Chem. Soc. Perkin Trans. 1 1997 firmed the location of the silyl group in 5 and hence the corresponding location in 4.The secondary hydroxy group in 5 was readily oxidised using either pyridinium chlorochromate (PCC) tetrapropylammonium perruthenate–N-methylmorpholine N-oxide (TPAP– MNO) or pyridinium dichromate (PDC) in the presence of 4 Å activated molecular sieves. The latter reaction proceeded in the highest yield (87%) to give the ketone 6. This compound is acidsensitive and so was purified by recrystallisation from hexane. Ketone 6 is the key intermediate in the synthesis of both (2R)-2-bromodehydroquinic acid 8 and (2R)-2-fluorodehydroquinic acid 10 (Scheme 2). For the synthesis of (2R)-2- bromodehydroquinic acid the bromine is introduced stereoselectively using dioxane dibromide10 to afford the axiallybrominated derivative 7 (89%).In the NMR spectrum of 7 the axial bromine causes a downfield shift in the signal for the hydrogen 1,3-diaxial to it (2ax-H) from d 2.86 in 6 to d 3.33. The isolation of a single diastereoisomer of 7 is presumed to be due to preferential bromination on the side of the ketone 6 opposite to the bridging lactone group. The TBDMS protecting group of 7 was removed and the lactone opened by mild acid hydrolysis (HOAc–H2O–THF) at 40 8C to give the required (2R)-2-bromodehydroquinic acid 8 in 95% yield. The equatorial position of the bromine was confirmed by NMR spectroscopy. Irradiation of 2-H led to enhancement of the signals for 4-H (6%) and 6ax-H (4%). Correspondingly irradiation of 4-H enhanced the signals for 2-H (6%) and 6ax-H (3%). The configuration at C-2 (C-6 in compound 7) is unchanged in going from 7 to 8 it is simply the cleaving of the lactone which allows the ring to flip to the other chair conformation.(2R)-2-Fluorodehydroquinic acid 10 was synthesised from the protected ketone 6 in two steps. The silyl enol ether was made using trimethylsilyl trifluoromethanesulfonate and reacted directly with Selectfluor‚ 9 in DMF to give the protected fluoro ketone 9 in 89% yield. This was deprotected in aqueous Scheme 2 Reagents conditions and yields (i) Br2?dioxane Et2O room temp. (89%); (ii) AcOH THF H2O 40 8C (95%); (iii) (a) TMSOTf Et3N toluene reflux (b) Selectfluor‚ DMF room temp. (89%); (iv) AcOH H2O 50 8C (90%) acetic acid to give 10 (90%). The equatorial position of the fluorine was confirmed by NMR spectroscopy. The fluorine has a geminal coupling to 2-H of 47 Hz and a W-coupling to 6eq-H of 8 Hz.Irradiation of 2-H led to enhancement of the signals for 4-H (6%) and 6ax-H (4%). Correspondingly irradiation of 4-H enhanced the signals for 2-H (6%) and 6ax-H (3%). (2R)-2-Bromodehydroquinic acid and (2R)-2-fluorodehydroquinic acid are stable in either water or acetone at 4 8C. However upon heating to over 80 8C quantitative dehydrohalogenation and aromatisation yield 3,4,5-trihydroxybenzoic acid. The syntheses of (2R)-2-bromodehydroquinic acid 8 and (2R)-2-fluorodehydroquinic acid 10 are both short and highyielding especially in light of the problems encountered in the synthesis of the related 2-bromoshikimic acid 4 and 2-fluoroshikimic acid.5 Preliminary studies show that both 8 and 10 are inhibitors for dehydroquinate dehydratase the third enzyme on the shikimate pathway.Full details of these biological studies will be published elsewhere. Experimental General NMR Spectra were recorded on either a Bruker WM-250 WM-400 DPX-250 or DPX-500 NMR spectrometer in deuteriated solvents with tetramethylsilane as an internal standard. J Values are given in Hz. Melting points were determined on a Buchi 510 or Reichert melting points apparatus and are uncorrected. IR Spectra were recorded on a Perkin-Elmer 1310 infrared spectrometer or a 1710 Fourier Transform spectrometer as Nujol mulls unless otherwise indicated. Mass spectra were recorded on a Kratos MS890 double-focussing magnetic sector apparatus (for EI CI and FAB). Optical rotations were measured on an AA-10 automatic polarimeter (Optical Activity Ltd.); [a]D values are given in 1021 deg cm2 g21.All organic solvents were freshly distilled prior to use. Dichloromethane triethylamine toluene and hexane were dried over calcium hydride. Methanol was dried over potassium carbonate. Diethyl ether was dried over lithium aluminium hydride. Analytical thin layer chromatography was carried out on commercial Kieselgel 60 0.25 mm silica plates. Spots were visualised by UV absorbance at 254 nm iodine potasium permanganate(VII) or cerium molybdate solution. Flash chromatography was carried out using 230–400 mesh Kieselgel 60 silica. The carboxylic acids were purified by HPLC on a preparative (300 mm × 16 mm) Bio-Rad Aminex Ion Exclusion HPX-87H Organic Acids column eluting with aqueous formic acid (50 mM) at a flow rate of 1.2 cm3 min21 with the UV detector set at 277 nm.(1S,3R,4R,5R)-4,5-Benzylidenedioxy-1-hydroxycyclohexane- 1,3-carbolactone 2 A mixture of (2)-quinic acid 1 (4.94 g 25.7 mmol) distilled benzaldehyde (3.9 cm3 38.6 mmol) and toluene-p-sulfonic acid (253 mg 1.3 mmol) was heated at reflux in toluene (50 cm3) in an apparatus fitted with a Dean–Stark trap for 22 h. The solution was allowed to cool and the toluene evaporated at reduced pressure. The oily residue was taken up in diethyl ether and decanted from the solid. The crude mixture was purified by column chromatography on silica gel eluting with ethyl acetate– light petroleum (bp 40–60 8C) (1 1) to give the benzylidene carbolactones 2 (5.31 g 79%) as a mixture of diastereoisomers at the benzylic carbon in a ratio of 2.2 1. On cooling the viscous oil crystallised.Recrystallisation from diethyl ether gave the major diastereoisomer (with the R configuration at the benzylic centre) of carbolactone 2 as white needles mp 100–101 8C (lit.,7 95 8C); RF 0.46 [ethyl acetate–light petroleum (bp 40–60 8C) 1 1] (Found C 63.9; H 5.4. C14H14O5 requires C 64.1; H 5.4%); nmax(CH2Cl2)/cm21 3540 (free OH) 3420 (H-bonded OH) 1800 (C]] O) and 1470 (Ar C–C); dH(250 MHz; CDCl3) 7.51–7.36 (5 H m Ph) 5.75 (1 H s PhCHO2) 4.81 (1 H dd J J. Chem. Soc. Perkin Trans. 1 1997 627 6.1 and 2.1 3-H) 4.52 (1 H td J 7.0 and 2.7 5-H) 4.37 (1 H dt J 7.0 and 2.1 4-H) 2.91 (1 H br s OH) 2.78 (1 H d J 11.9 2ax-H) 2.46 (1 H ddd J 15.1 7.0 and 2.1 6eq-H) 2.36 (1 H dd J 15.1 and 2.7 6ax-H) and 2.34 (1 H ddt J 11.9 6.1 and 2.1 2eq-H); dC(62 MHz; CDCl3) 178.9 135.4 129.9 128.6 126.6 103.7 75.5 72.9 72.7 71.4 37.7 and 34.4; m/z (EI+) 262 (M+) 261 [(M 2 H)+] and 105 [(PhCO)+] (Found M+ 262.0820.C14H14O5 requires M 262.0841). (1S,3R,4R,5R)-1,4,5-Trihydroxycyclohexane-1,3-carbolactone 3 To 500 mg of palladium on charcoal (10%) under a hydrogen atmosphere was added glacial acetic acid (10 cm3). After 10 min a solution of the acetal 2 (5 g 19.0 mol) in glacial acetic acid (40 cm3) was added. The system was evacuated and kept under a hydrogen atmosphere until reduction was complete as judged by TLC (48 h). The hydrogen was evacuated the suspension filtered over Celite and washed with acetic acid (50 cm3) and methanol (50 cm3). The solvent was removed under reduced pressure and the product was recrystallised from acetic acid to afford 3.09 g (94%) of the hydroxylactone 3 as white prisms mp 184–185 8C (lit.,8 185–189 8C); nmax/cm21 3000–3560 (OH) and 1780 (C]] O); dH(250 MHz; CD3OD) 4.91 (3 H br s OH) 4.75 (1 H dd J 4.9 and 6.0 3-H) 4.02 (1 H dd J 4.5 and 4.9 4-H) 3.74 (1 H ddd J 4.5 6.6 and 11.3 5-H) 2.51 (1 H d J 11.5 2ax-H) 2.26 (1 H ddd J 2.9 6.0 and 11.5 2eq-H) 2.07 (1 H ddd J 6.6 2.9 and 11.6 6eq-H) and 1.91 (1 H dd J 11.3 and 11.6 6ax-H); dC(62 MHz; CD3OD) 179.5 77.6 73.1 67.3 66.8 40.0 and 37.8.Selective monosilylation of the trihydroxylactone 3 Method A. To a stirred solution of the hydroxylactone 3 (1.83 g 10.52 mmol) 4-dimethylaminopyridine (DMAP) (180 mg 1.47 mmol) and butylammonium iodide (194 mg 0.53 mmol) in dry DMF (17 cm3) and dry triethylamine (1.8 cm3 12.62 mmol) at 0 8C under argon was added 1.82 g (12.1 mmol) of tert-butyldimethylsilyl chloride.The solution was stirred at this temperature for 30 min and then 5 h at room temp. The resultant suspension was diluted with ethyl acetate (100 cm3) and filtered over Celite. The solution was washed successively with 1 M HCl (100 cm3) and brine (3 × 100 cm3) dried (MgSO4) filtered and evaporated. The crude product (yellow solid) was purified by column chromatography on silica gel eluting with diethyl ether–hexane (1 1) to yield 2.40 g (79%) of monosilyl ether 4 and 82 mg (3%) of monosilyl ether 5 as white needles. Method B. To a stirred solution of the hydroxylactone 3 (1.02 g 5.86 mmol) DMAP (100 mg 0.82 mmol) and butylammonium iodide (108 mg 0.29 mmol) in dry DMF (9.6 cm3) and dry triethylamine (0.98 cm3 7.03 mmol) at room temp.under argon was added 1.01 g (6.73 mmol) of tert-butyldimethylsilyl chloride. The resultant solution was heated at 90 8C for 24 h and after cooling was diluted with ethyl acetate (100 cm3) and filtered over Celite. The solution was washed successively with 1 M HCl (100 cm3) and brine (3 × 100 cm3) dried (MgSO4) filtered and evaporated. The crude product was purified by column chromatography on silica gel eluting with diethyl ether– hexane (1 1 to 3 1) to yield 918 mg (54%) of monosilyl ether 5 and 505 mg (30%) of monosilyl ether 4 as white needles. (1R,3R,4S,5R)-5-tert-Butyldimethylsiloxy-1,4-dihydroxycyclohexane- 1,3-carbolactone 4. Mp 95–96 8C (from hexane) (Found C 54.12; H 8.45. C13H24SiO5 requires C 54.17; H 8.33%); [a]D 20 234 (c 1.1 in CH3OH); nmax/cm21 3300 (br OH) and 1780 (C]] O); dH(250 MHz; CDCl3) 4.85 (1 H dd J 6.0 and 4.7 3-H) 3.95 (1 H dd J 4.5 and 4.7 4-H) 3.86 (1 H ddd J 4.5 7.2 and 11.6 5-H) 3.00 (1 H s OH) 2.96 (1 H s OH) 2.59 (1 H d J 11.6 2ax-H) 2.28 (1 H ddd J 2.6 6.0 and 11.6 6eq- H) 1.89–2.06 (2 H m 6ax-H and 2eq-H) 0.88 [9 H s C(CH3)3] and 0.08 [6 H s Si(CH3)2]; dC(62 MHz; CDCl3) 178.1 76.3 71.7 67.0 65.6 40.1 36.4 25.6 17.9 24.7 and 25.0.(1S,3R,4R,5R)-4-tert-Butyldimethylsiloxy-1,5-dihydroxycyclohexane- 1,3-carbolactone 5. Mp 154–155 8C (from hexane) (Found C 54.21; H 8.39. C13H24O5Si requires C 54.17; H 8.33%); [a]D 20 224 (c 0.4 in CH3OH); nmax/cm21 3480 (OH) 3380 (OH) and 1800 (C]] O); dH(250 MHz; CDCl3) 4.65 (1 H dd J 6.0 and 4.2 3-H) 4.08 (1 H dd J 4.8 and 4.2 4-H) 3.80 (1 H dddd J 4.9 6.6 11.1 and 11.3 5-H) 2.99 (1 H s 1-OH) 2.50 (1 H d J 11.4 2ax-H) 2.29 (1 H ddd J 2.9 6.0 and 11.4 2eq-H) 2.17 (1 H ddd J 2.9 6.6 and 12.0 6eq-H) 2.09 (1 H d J 11.3 5-OH) 1.83 (1 H dd J 12.0 and 11.1 6ax-H) 0.92 [9 H s C(CH3)3] 0.15 (3 H s SiCH3) and 0.12 (3 H s SiCH3); dC(62 MHz; CDCl3) 177.9 (C) 76.3 (CH) 71.9 (C) 67.0 (CH) 65.8 (CH) 40.7 (CH2) 36.4 (CH2) 25.6 [C(CH3)3] 17.9 (C) 24.7 (SiCH3) and 25.0 (SiCH3).(1R,3R,4S)-4-tert-Butyldimethylsiloxy-1-hydroxy-5-oxocyclohexane- 1,3-carbolactone 6 To a stirred suspension of the alcohol 5 (232 mg 0.81 mmol) and 4 Å activated molecular sieves (300 mg) in dry dichloromethane (6 cm3) was added pyridinium dichromate (606 mg 1.61 mmol). The resultant suspension was stirred at room temp. for 2 h and then diluted with diethyl ether (60 cm3) and filtered over Celite. The solution was washed successively with HCl (5% 2 × 50 cm3) and brine (2 × 50 cm3) dried (MgSO4) filtered and evaporated.The product was recrystallised from hexane to afford 201 mg of the ketone 6 as white crystals (87%) mp 92–93 8C (Found C 54.46; H 7.84. C13H22SiO5 requires C 54.54; H 7.69%); [a]D 20 246 (c 0.4 in CH3OH); nmax/cm21 3350– 3500 (OH) 1810 (C]] O) and 1730 (C]] O); dH(62 MHz; CDCl3) 4.78 (1 H dd J 3.9 and 6.2 3-H) 4.05 (1 H ddd J 0.6 1.1 and 3.9 4-H) 3.10 (1 H d J 16.2 6ax-H) 2.95 (1 H s OH) 2.86 (1 H d J 12.1 2ax-H) 2.78 (1 H ddd J 1.1 3.1 and 16.2 6eq-H) 2.66 (1 H dddd J 0.6 3.1 6.2 and 12.1 2eq-H) 0.95 [9 H s C(CH3)3] 0.20 (3 H s SiCH3) and 0.16 (3 H s SiCH3); dC(250 MHz; CDCl3) 202.7 (C) 177.0 (C) 75.1 (CH) 71.4 (C) 70.6 (CH) 50.0 (CH2) 35.8 (CH2) 25.5 [C(CH3)3] 16.0 (C) 24.7 (SiCH3) and 25.3 (SiCH3); m/z (FAB+ve) 287 (MH+) (Found MH+ 287.1328.C13H23SiO5 requires M 287.1315). (1S,3R,4S,6R)-6-Bromo-4-tert-butyldimethylsiloxy-1-hydroxy- 5-oxocyclohexane-1,3-carbolactone 7 To a stirred solution of the ketone 6 (328 mg 1.15 mmol) in dry diethyl ether (30 cm3) under argon was added freshly made dioxane dibromide10 (313 mg 1.26 mmol). The red solution was stirred at room temp. until decoloration (2 h) diluted with diethyl ether (30 cm3) and washed successively with aqueous sodium metabisulfite (5% 30 cm3) aqueous sodium hydrogen carbonate (5% 30 cm3) and water (30 cm3). The organic layer was dried (MgSO4) filtered and evaporated. The product was recrystallised from hexane to afford the bromo ketone 7 as white needles (371 mg 89%) mp 124–125 8C (Found C 42.68; H 5.78.C13H21BrSiO5 requires C 42.74; H 5.75%); [a]D 20 2203 (c 0.4 in CH3OH); nmax/cm21 3540 (OH) 1820 (C]] O) and 1725 (C]] O); lmax(EtOH)/nm 238 and 339 (e/dm3 mol21 cm21 832 and 117); dH(250 MHz; CDCl3) 4.79 (1 H dd J 4.1 and 6.3 3-H) 4.35 (1 H dd J 1.2 and 2.5 6-H) 4.19 (1 H ddd J 0.9 1.2 and 4.1 4-H) 3.78 (1 H s OH) 3.33 (1 H d J 12.7 2ax-H) 2.55 (1 H dddd J 0.9 2.5 6.3 and 12.7 2eq-H) 0.95 [9 H s C(CH3)3] 0.26 (3 H s SiCH3) and 0.19 (3 H s SiCH3); dC(100 MHz; CDCl3) 198.3 (C) 172.8 (C) 76.4 (CH) 74.7 (C) 74.0 (CH) 71.0 (CH) 51.9 (CH) 32.7 (CH2) 25.3 [C(CH3)3] 17.9 (C) 25.3 (SiCH3) and 25.5 (SiCH3); m/z (FAB+ve) 365 (MH+) (Found MH+ 365.0420. C13H22BrSiO5 requires M 365.0420). (1S,2R,4S,5R)-2-Bromo-1,4,5-trihydroxy-3-oxocyclohexanecarboxylic acid [(2R)-2-bromodehydroquinic acid] 8 To a solution of the bromo ketone 7 (400 mg 1.10 mmol) in acetic acid (4 cm3) was added water (1 cm3) and the solution stirred at 40 8C for 72 h.The solution was lyophilised and the residue partitioned between ethyl acetate (25 cm3) and water (25 cm3). The aqueous phase was washed with ethyl acetate (25 cm3) and lyophilised to give the crude product. Recrystallisation 628 J. Chem. Soc. Perkin Trans. 1 1997 from ethyl acetate–hexane (50 50) yielded 2-bromodehydroquinic acid 8 (280 mg 95%) mp 112–114 8C (decomp.) (Found C 31.39; H 3.31. C7H9BrO6 requires C 31.23; H 3.35%); [a]D 20 236 (c 1.1 in CH3OH); nmax/cm21 3420 (OH) 3280 (OH) 1740 (C]] O) and 1700 (C]] O); dH(250 MHz; [2H6]acetone) 5.55 (1 H d J 0.9 2-H) 4.80 (3 H br s OH) 4.40 (1 H dd J 0.9 and 9.2 4-H) 3.96 (1 H ddd J 5.6 9.2 and 10.8 5-H) and 2.38–2.48 (2 H m 6-H); dC(62 MHz; [2H6]acetone) 197.8 (CH) 173.1 (C) 81.9 (CH) 77.9 (CH) 72.3 (CH) 61.7 (CH) and 40.9 (CH2); m/z (CI NH4 +) 268 266 252 250 188 and 172.(1S,3R,4S,6R)-6-Fluoro-4-(tert-butyldimethylsiloxy)-1- hydroxy-5-o